Momelotinib ( MMB ), an oral JAK1/2 and ACVR1/ALK2 inhibitor, has shown clinical activity on myelofibrosis symptoms, red blood cell ( RBC ) transfusion requirements ( anemia ), and spleen volume in the SIMPLIFY trials.
MOMENTUM is a pivotal phase 3 study of myelofibrosis patients previously treated with a JAK inhibitor ( JAKi ) tested Momelotinib versus Danazol on key symptom, anemia, and spleen volume endpoints at 24 weeks.
Participant eligibility included: primary or post-essential thrombocythemia / polycythemia vera [ post-ET/PV ] myelofibrosis; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score ( MFSAF TSS ) 10 or more; Hgb less than 10 g/dL; prior JAKi for 90 or more days, or 28 or more days if RBC transfusions 4 or more units in 8 weeks or grade 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen 5 or more cm.
Subjects were randomized 2:1 to Momelotinib 200 mg QD plus Danazol placebo or Danazol 600 mg QD plus MMB placebo for 24 weeks, after which patients could receive open-label Momelotinib.
The primary endpoint was TSS response ( greater than or equal to 50% reduction from baseline ) rate at week 24.
Secondary endpoints, assessed sequentially at week 24, were RBC transfusion independence rate, splenic response rate ( SRR; greater than or equal to 25% reduction in volume from baseline ), change from baseline in TSS, SRR ( greater than or equal to 35% reduction from baseline ) and rate of zero transfusions since baseline.
94 of 130 ( 72% ) Momelotinib patients and 38 of 65 ( 58% ) Danazol patients completed the 24-week randomized treatment ( RT ) phase.
Median baseline TSS were 28 ( MMB ) and 26 ( DAN ), Hgb were 8.1 ( MMB ) and 7.9 ( DAN ) g/dL, and platelets were 97 ( MMB ) and 94 ( DAN ) x109/L.
Baseline transfusion independence was 13% ( MMB ) and 15% ( DAN ).
Prior JAKi was Ruxolitinib in 195 patients ( 100% ) and Fedratinib in 9 patients ( 5% ).
All primary and key secondary endpoints were met.
Most common grade 3 or more TEAEs in the RT phase of the study were thrombocytopenia ( MMB, 22%; DAN, 12% ) and anemia ( MMB, 8%; DAN, 11% ).
Grade 3 or more infections occurred in 15% of Momelotinib and 17% of Danazol patients.
Peripheral neuropathy occurred in 5 ( 4% ) of Momelotinib ( all grade 2 or less ) and 1 ( 2% ) of Danazol ( grade 2 or less ) patients in the RT phase, and none discontinued study drug.
Overall, TEAEs led to study drug discontinuation in 18% of Momelotinib and 23% of Danazol patients in RT phase.
A trend toward improved overall survival up to week 24 was seen with Momelotinib vs Danazol ( hazard ratio, HR=0.506, p=0.0719 ).
In conclusion, in symptomatic and anemic patients with myelofibrosis, Momelotinib was superior to Danazol for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival.
Momelotinib may address a critical unmet need, particularly in myelofibrosis patients with anemia. ( Xagena )
Mesa RA et al, Journal of Clinical Oncology 2022; 40, Issue 16_suppl